Tirbanibulin Ointment 1% as a Novel Treatment for Actinic Keratosis: Phase 1 and 2 Results

November 2020 | Volume 19 | Issue 11 | Original Article | 1093 | Copyright © November 2020


Published online November 4, 2020

Steven Kempers MDa, Janet DuBois MDb, Seth Forman MDc, Amy Poon BS MAd, Eva Cutler BS BAd, Hui Wang PhDd, David Cutler MD FRCP(C)d, Jane Fang MDd, Rudolf Kwan MBBS MRCPd

aMinnesota Clinical Study Center, New Brighton, MN
bDermResearch, Austin, TX
cForCare Medical Center, Tampa, FL
dAthenex, Inc., Buffalo, NY

Abstract
Background: Current field-directed treatments of actinic keratosis (AK), a pre-malignant condition, are often limited by severe local reactions and/or complex treatment. Tirbanibulin, a novel potent anti-proliferative synthetic agent that inhibits tubulin polymerization and Src kinase signalling, is being developed as a convenient, safe, and effective field treatment of actinic keratosis.
Hypothesis: A short course of tirbanibulin ointment 1% safely reduces AK lesions.
Methods: In the Phase 1 study, 4 treatment cohorts with forearm lesions received tirbanibulin ointment 1% over 25 or 100 cm2 once daily for 3 or 5 days and were evaluated through day 45. In the Phase 2 study, 2 treatment cohorts with face or scalp lesions received tirbanibulin ointment 1% once daily for 3 or 5 days over 25 cm2 and were evaluated through day 57. Lesion reductions, clearance rates, safety, and pharmacokinetics were assessed.
Results: Forearm AK lesions were reduced by day 45 in all Phase 1 cohorts (N=30). Complete AK clearance at day 57 for face/scalp AK lesions in Phase 2 cohorts (N=168) was demonstrated in 43% and 32% of participants of the 5-day and 3-day cohorts, respectively. Adverse reactions were mainly transient mild local erythema and flaking/scaling, pruritus, and pain. Tirbanibulin plasma concentrations were low or undetectable.
Conclusion: Tirbanibulin ointment 1% was well tolerated and active in AK reduction. Based on activity, the 5-day regimen was selected for Phase 3 development.
Clinicaltrials.gov: NCT02337205; NCT02838628

J Drugs Dermatol. 2020;19(11):1093-1100. doi:10.36849/JDD.2020.5576

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INTRODUCTION

Actinic keratosis (AK) is a pre-malignant condition, associated with prolonged ultraviolet damage predominantly on the face/scalp, trunk, and extremities.1,2 AK affects ~58 million individuals in the US,3 and typically occurs in males, fair-skinned individuals, and those of advancing age.4,5 As the progression of AK to invasive squamous cell carcinoma (iSCC) is unpredictable, the generally accepted approach is to treat all AK.6 Current treatments are lesion- or field-directed therapies.1 Lesion-directed therapies are used when the lesion burden is low; but these modalities can cause scarring and long-term pigmentary changes.1,7 Field-directed therapies are used to treat multiple lesions, large areas, and subclinical lesions.1,7 Commonly used topical treatments, while effective, frequently cause moderate-to-severe application-site reactions and deleterious effects on uninvolved skin,7-11 which are often considered unacceptable to patients. Moreover, many of these treatments have lengthy or cumbersome dosing regimens that may undermine treatment compliance and compromise efficacy.12,13 Given the disadvantages of available topical therapies, there is a need to develop an agent that has low potential for severe local reactions, effective AK clearance, and convenient dosing.

Tirbanibulin is a synthetic, first-in-class, potent anti-proliferative agent that inhibits tubulin polymerization and disrupts Src kinase signaling14 that are upregulated in AK and iSCC.15-17 Tirbanibulin also promotes the induction of p53, G2/M arrest of proliferating cell populations, and subsequent apoptosis via stimulation of caspase-3 and poly (ADP-ribose) polymerase cleavage.14 In vitro, tirbanibulin demonstrated potent inhibition of the growth of primary human keratinocytes and several melanoma cell lines (GI50 ≤50 nM).14 Preclinical in vitro and in vivo toxicity and dermal irritation studies also supported the further development of tirbanibulin ointment 1% in clinical trials (unpublished data). We hypothesized that a short course of tirbanibulin ointment 1% would be locally safe and active in clearing AK through its mechanism of action that promotes anti-proliferative and pro-apoptotic effects on the actively dividing dysplastic keratinocytes. Here, we describe the results of two early-phase studies in testing this hypothesis.